The JAK tyrosine kinases and STAT transcription factors are required in almost all signaling pathways that respond to cytokines and have a role in many pathways that respond to growth factors. Thus, it is not surprising that defects in pathways governed by JAKs and STATs occur in many diseases, for example, cancer (STAT3 is an oncogene and STAT1 is a tumor suppressor) and immune deficiency syndromes. Although the STATs are latent transcription factors that are activated by tyrosine phosphorylation, serine phosphorylation of some of the STATs is also vital for their function, and the mechanisms are now coming under more intense investigation. Exciting new research has shown essential roles for STAT family members in slime molds, zebrafish and insects, testifying to their importance in many different biological processes throughout evolution. Activated STATs are transcription factors that must gain access to the nucleus and must interact with the basal transcriptional machinery; these aspects of STAT function are under intensive investigation. Recent crystal structures of STATs bound to their target DNA sequences have opened the door to a rich array of structure-function analyses. Activated STAT dimers mediate gene expression both positively and negatively, and recent work has even shown a role for unphosphorylated STAT1 monomers in facilitating the constitutive expression of certain genes. The goals of this Keystone Symposium are to cross-fertilize a very wide range of research projects in an exciting and rapidly evolving field that has important implications in understanding human health and disease.